The invention relates to the use of at least one overexpression inhibitor of DNA repair genes and/or oncogenes for producing a drug to increase the apoptotic effect of cytostatics after chemotherapy.
Cancer diseases in humans are one of the most frequent causes of death and chemotherapy is the most frequent treatment method. The inadequate chances for a cure by a chemotherapy are based on the occurrence of resistances. These resistances have their root in the fact that cytostatics influence the expression of genes and have a genotoxic effect, i.e. induce mutations, gene amplifications and recombinations and hence destabilise the genome. In this way, a chemotherapy induces or selects resistant cancer cells. Often oncogenes, such as e.g. Ras, Bc12, Bcr-abl, Myc, ErbB2 and others, are affected by such effects induced by cytostatics. Wrongly regulated expression of genes in conjunction with DNA repair and recombination also contributes to chemoresistance (e.g. p53 gene, BRCA1/2, UBE2N, APEX and Rad51), furthermore enzymes which metabolise and bioactivate cytostatics (e.g. DHFR, DT-diaphorase (DT-D), or proteins which convey cytostatics (e.g. MDR1).
Most cytostatics eliminate tumour cells in that they induce apoptosis. Apoptosis is a form of programmed cell death which was described firstly in Kerr, J. F. et al., Br J Cancer, 26(4) (1972); 239-257. In contrast to necrosis, apoptosis is a physiological form of cell death. These two forms of cell death can be differentiated by means of differences between necrosis and apoptosis. Apoptosis has defined morphological and biochemical characteristics which occur successively as events of an ordered cascade. The continuous process can be divided into phases. Morphological characteristics of apoptosis are core chromatin condensation (karyopyknosis), shrinkage of cytoplasm, formation of apoptotic vesicles and finally apoptotic bodies. Tumour cells can prevent this by overactivation of survival mechanisms. Mechanisms of chemoresistance therefore also comprise anti-apoptotic acting genes, such as e.g. STAT3, the activated “signal transducer and activator of transcription 3” or JUN-D.
In 1995 effects of specific hormones and 5-substituted nucleosides which were hitherto unknown were discovered. These suppress the 2-amino-6-mercaptopurine (AMP)-induced SV40 amplification in cells of the Chinese hamster (Fahrig, R. et al., Mutat Res., 356 (2), 1996, 217-224) and triethylene melamine-induced recombination in yeasts (Fahrig, R., Mutat Res, 372 (1), 1996, 133-139). In EP 0 806 956 B1, the treatment of leukaemia cells of the mouse with 5-substituted nucleosides is described, the doxorubicin (adriamycin)-induced Mdr1 gene amplification and chemoresistance having been inhibited.
In the in vitro tests implemented to date, 5-substituted nucleosides (i.e. base analogues) have always been applied together with one or more cytostatics.